Designing for Brain Health: A CREB-Based Theoretical Framework Linking Built-Environment Features to Hippocampal Neuroplasticity

Cognitive decline is a global public health challenge, yet the built environments where humans spend 90% of their time are only now being recognized as a means of preventive intervention. This paper presents a mechanistic framework describing how environmental and design features may influence hippocampal neuroplasticity, offering architects an evidence-based foundation for supporting brain health. We describe how eight environmental pathways, five activating features (design that promotes movement, enrichment, orientation features, daylight, views of nature) and three inhibiting features (air quality, noise, visual pattern stress) are hypothesized to converge on cAMP Response Element-Binding protein (CREB), a representative transcriptional integrator regulating Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus. BDNF is a protein implicated in brain health outcomes including synaptic plasticity, neuronal survival, neurogenesis and cognitive function. Synthesizing evidence from neuroscience, exercise physiology, environmental psychology, toxicology, and visual neuroscience, we grade evidence strength for each pathway and identify the specific design variables involved. Evidence strength varies markedly across pathways: movement and enrichment rest on direct experimental and meta-analytic data, including human studies; air quality and noise rest on direct mechanistic evidence largely from animal and exposure studies; orientation features, daylight, and views of nature rest on indirect mechanistic inference; and visual pattern stress remains hypothesis-generating at the architectural scale. Enrichment and active design pathways show the strongest evidence for CREB activation, while noise, air quality, and non-natural visual patterns are associated with CREB inhibition. From this framework, we derive a consolidated set of design features organized by pathway, evidence strength, and temporal impact on brain health outcomes. These range from immediate synaptic plasticity to long-term neuroprotection. This mechanistic model offers a roadmap for a longer-term research program and outlines the formal structure required for future computational implementations. The framework can serve as a bridge connecting neuroscience to the emerging global movement on brain health that positions the built environment as an underutilized lever for supporting cognitive health across the lifespan.